Field of the Invention and Prior Art
The present invention relates to novel prolonged release formulations or compositions, e.g., tablet, granule, lozenge, capsule, or like formulations, containing a gel-forming dietary fiber and a drug or other active therapeutic agent plus certain essential disintegrants.
Many drugs and vitamins must be released in a uniform and/or continuous manner over a period of time. Water-soluble vitamins, for example, unless placed into a time-release form, are almost immediately released into the bloodstream once they dissolve in the stomach. Aspirin is frequently coated to minimize gastric upset and release the drug over a period of time. Sustained-release dosage forms also avoid the necessity of frequent administration of the drug while, at the same time, achieving a desired blood level of active ingredient.
Various cellulose derivatives have been used to provide rapid disintegration of tablets, such as in U.S. Pat. No. 3,266,992, which describes the use of methylcellulose, sodium carboxymethylcellulose and hydroxyethylcellulose for such purpose. However, in contrast, hydroxypropylmethylcellulose in enteric coatings has been disclosed in U.S. Pat. No. 2,887,440 to prevent disintegration of a tablet core and delay release of the active ingredients.
U.S. Pat. No. 3,870,790 discloses a method of preparing a long-acting buccal composition for administering a therapeutic agent using an effective amount of hydroxypropylmethylcellulose which has been subjected to controlled humidity. Other processes for treating cellulose derivatives are described in U.S. Pat. Nos. 4,226,849, 4,357,469, 4,369,172, 4,389,393, 4,540,566, 4,795,327, and 4,849,229, the treated cellulose derivatives then being used in a solid drug dosage unit form to produce a controlled and prolonged-release pattern of a drug upon administration thereof.
For purposes of definition in this specification, the term "dietary fiber" is defined as "remnants of plant cells resistant to hydrolysis by the alimentary enzymes of man, the group of substances that remain in the ileum but are partly hydrolyzed by bacteria in the colon", according to JAMA 262, No. 4, 542-546 (Jul. 28, 1989) in the Council Report entitled "Dietary Fiber and Health", at page 542. This article, moreover, gives considerable information as to what constitutes a "dietary fiber" and is accordingly incorporated herein by reference.
Gel-forming dietary fibers include mucilages, plant gums, pectins or pectic substances, and lignin, all of which are endogenous compounds of plant materials which are resistant to digestion by enzymes in the monogastric stomach or small intestine. Chemically, nearly all of these plant materials are carbohydrates composed of repeating monosaccharide (sugar) units. Disaccharides have two sugar units, oligosaccharides three to twelve, and polysaccharides may contain a million or more. The water-soluble fractions of these substances form gels in the stomach and intestinal tract and are known to lower serum cholesterol.
Gums and mucilages have no common structure but are polysaccharides containing several sugars with alternating monomer structures and may or may not contain uronic acids. There are many gums found in plants and cereal grains. Guar and locust bean gums are galactomannans, whereas gum arabic is an acidic polymer of galactose and rhamnose. Oat and barley contain gums, but are not practical for use in the present application because of the low percentage of active gum per weight volume. Most of the gums in the present application are effective at much lower dosages. Suitable gums include, inter alia, besides guar gum, the following: locust bean gum, acacia gum, gum arabic, xanthan gum, carrageenan gum, karaya gum, tragacanth gum, and ghatti gum.
Pectic substances or pectins are mixtures of polysaccharides of partially methylated and 1,4-D galacturonic acid units with side chains containing arabinose, galactose, xylose, and rhamnose. They are contained in many fruits and vegetables as well as in other plants.
Other suitable gel-forming dietary fibers include psyllium husks, algal polysaccharides, glucomannan, and agar, to name a few. Lignin is a non-carbohydrate polymer of aromatic plant alcohols comprising oxygenated phenylpropane units. As a plant matures, more lignin is produced, which acts as a sort of cement as it hardens and holds together other plant cell wall constituents. Lignin passes through the digestive tract with very little change.
As already mentioned, a recent review of dietary fiber which mentions these substances is contained in the following reference: Dietary Fiber and Health, JAMA 262: No. 4, 542-546 (1989), from the Council on Scientific Affairs, American Medical Association.
Some gel-forming fibers such as guar gum are used as binders and disintegrators for compressed tablets, but at fairly low levels. At higher levels, these gel-forming fibers and gums are known not to dissolve properly when compressed into tablets.
Various unsuccessful attempts have been made to solve the problem of improper and incomplete dissolution of guar gum tablets. EPA 0080673 describes these problems in detail, and discloses the use of 5 to 30% of highly-dispersed silica gel in guar tablets. Normally used tablet disintegrants or additives such as polyvinylpyrrolidone (crosslinking agent), sodium carboxymethyl-starch, cornstarch, microcrystalline cellulose, and so on, do not lead to satisfactory results. Hard tablets are produced which do not swell properly, and which form an impenetrable layer of gel around a powder core which may pass through the gastrointestinal tract undissolved and nearly intact.
U.S. Pat. No. 4,824,672 describes the use of mineral carbonates to enhance dispersion of gel-forming dietary fibers in orally-administrable pharmaceutical compositions for use in reducing serum cholesterol levels. Such compositions have proved to be effective in use for their intended purpose of dispersing the fibers, but do not disclose or suggest a method or means for providing a controllable prolonged-release unit dosage formulation of a biologically-absorbable therapeutic agent or drug.
The foregoing EPO 0080673 mentions the employment of citric acid with guar gum tablets. The citric acid and sweeteners were used, according to that disclosure, to improve the acceptability of the tablets if they were to be chewed. Accordingly, the citric acid was there used to provide flavor and an aromatic quality to the product. Such formulations did not contain a mineral carbonate or bicarbonate and, moreover, when a carboxylic acid such as citric acid was employed in the compositions of that invention, "the acid is coated with 1 to 20% of a water-repellent agent based on the weight of the acid", reportedly to provide increased storage stability of the product.
It is apparent that the prior art has not provided any suitable prolonged-release unit dosage formulation for the prolonged release of an effective dose of a biologically-absorbable therapeutic agent or drug, much less such a prolonged-release unit dosage formulation which employs or embodies a gel-forming dietary fiber as an essential part of the matrix, fundamentally because of the fact that the swelling and balling and plug formation of such gel-forming dietary fibers has heretofore been considered an insurmountable disadvantage, insofar as the acid of the stomach does not readily or uniformly dissolve dietary fiber formulations, especially when in unit dosage form such as a tablet, granule, capsule, lozenge, or the like, for which reason release of any therapeutic agent or drug which may have been combined therewith was unpredictable and non-uniform and generally insufficiently rapid to cause or permit release of all of the drug or other therapeutic agent content thereof while the unit dosage formulation was present in the gastrointestinal tract.
According to my previous invention of U.S. Ser. No. 07/440,730, now U.S. Pat. No. 5,096,714, the entire disclosure of which copending application is hereby referred to and, by reference, made a part hereof, however, excellent prolonged-release unit dosage formulations were provided, which consisted essentially of an effective dose of the selected biologically-absorbable therapeutic agent or drug, a gel-forming dietary fiber, and a physiologically-acceptable edible acid, preferably a food-grade organic acid or phosphoric acid, and a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably a mineral carbonate or bicarbonate which releases carbon dioxide upon ingestion. According to my previous patent, as stated therein
"when a biological liquid begins to penetrate or wick into the prolonged-release unit dosage formulation, it dissolves the acid and mineral salt present therein, which react together to cause a rapid evolution of gas, e.g., carbon dioxide, which cannot be effected using either stomach acid alone or the mineral salt alone. This rapid evolution of gas breaks up the prolonged-release unit dosage form, e.g., tablet, granule, capsule, lozenge, or the like, before a surface layer of gel can form around the unit dosage form, especially a tablet, from the normal reaction of the gel-forming dietary fiber, which surface layer of gel would seal the unit dosage form off from further hydration and disintegration. As already stated, stomach acid alone is not sufficiently rapid acting and is furthermore outside of the unit dosage form, so that it is necessary to have both the physiologically-acceptable edible acid and the mineral salt which releases a physiologically-acceptable gas upon ingestion, inside the tablet, granule, capsule, lozenge, or the like, or dispersed throughout the tablet, granule, capsule, lozenge, or other unit dosage form, to increase the speed of hydration of the drug or other therapeutic agent contained in the unit dosage formulation. According to the invention, the gel produced by the gel-forming dietary fiber modulates the release of the drug, but does not prevent the drug from being biologically absorbed, inhibition of disintegration by formation of a gel coating around the unit dosage formulation by the gel-forming dietary fiber being prevented by the evolution of a physiologically-acceptable gas by virtue of the combined action of the acid and mineral salt within the unit dosage formulation itself upon contact with biological fluids, e.g., those of the gastrointestinal tract." PA1 composition wherein the gas released is carbon dioxide; such a PA1 composition wherein the mineral salt is a mineral carbonate or bicarbonate; such a PA1 composition wherein the mineral salt is calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; such a PA1 composition wherein the acid is present in amount of about 1% to about 50% by weight; such a PA1 composition wherein the acid is a food-grade organic acid or phosphoric acid; such a PA1 composition wherein the gel-forming dietary fiber comprises about 30-40% by weight of the composition; such a PA1 composition wherein a soluble sugar is present in an amount of about 1% to about 12% by weight of the composition; such a PA1 composition wherein the gel-forming fiber is psyllium husk powder, guar gum, locust bean gum, acacia gum, gum arabic, xanthan gum, carrageenan gum, karaya gum, tragacanth gum, ghatti gum, pectin, a pectic substance, an algal polysaccharide, glucomannan, agar, or lignin, or a combination of more than one thereof; such a PA1 composition wherein the drug or therapeutic agent is in granular form, with a hydrocolloid film coating about the granules thereof; such a PA1 composition wherein the hydrocolloid is a cellulose polymer, gum acacia, guar gum, xanthan gum, gum tragacanth, a carrageenan, or an alginate, or a combination of more than one thereof; such a PA1 composition wherein the drug or therapeutic agent is in granular form, with a hydrocolloid coating about the granules thereof, and wherein both the gel-forming fiber and the drug or therapeutic agent are coated with a film of a hydrocolloid which is cellulose polymer, gum acacia, guar gum, xanthan gum, gum tragacanth, a carrageenan, or an alginate, or a combination of more than one thereof; such a PA1 composition wherein at least the gel-forming dietary fiber is in the form of granules which are coated with a cellulose polymer coating, the composition optionally being compressed into a tablet form; such a PA1 composition wherein the drug or therapeutic agent is in granular form, the granules being coated with a film of a cellulose polymer, the composition optionally being compressed into a tablet form; such a PA1 composition wherein the drug or therapeutic agent is niacin; such a PA1 composition wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form; such a PA1 composition in tablet form; and such a PA1 composition wherein the drug or therapeutic agent is an analgesic, an antihypercholesterolemic, a vitamin, a stimulant, an appetite suppressant, a mineral supplement, or a therapeutic peptide. PA1 method wherein the gas released is carbon dioxide; such a PA1 method wherein the mineral salt is a mineral carbonate or bicarbonate; such a PA1 method wherein the mineral salt is calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; such a PA1 method wherein the acid is present in amount of about 1% to about 50% by weight; such a PA1 method wherein the acid is a food-grade organic acid or phosphoric acid; such a PA1 method wherein the gel-forming dietary fiber comprises about 30-40% by weight of the composition; such a PA1 method wherein a soluble sugar is present in an amount of about 1% to about 12% by weight of the composition; such a PA1 method wherein the gel-forming fiber is psyllium husk powder, guar gum, locust bean gum, acacia gum, gum arabic, xanthan gum, carrageenan gum, karaya gum, tragacanth gum, ghatti gum, pectin, a pectic substance, an algal polysaccharide, glucomannan, agar, or lignin, or a combination of more than one thereof; such a PA1 method wherein the drug or therapeutic agent is in granular form, with a hydrocolloid film coating about the granules thereof; such a PA1 method wherein the hydrocolloid is a cellulose polymer, gum acacia, guar gum, xanthan gum, gum tragacanth, a carrageenan, or an alginate, or a combination of more than one thereof; such a PA1 method wherein the drug or therapeutic agent is in granular form, with a hydrocolloid coating about the granules thereof, and wherein both the gel-forming fiber and the drug or therapeutic agent are coated with a film of a hydrocolloid which is cellulose polymer, gum acacia, guar gum, xanthan gum, gum tragacanth, a carrageenan, or an alginate, or a combination of more than one thereof; such a PA1 method wherein the gel-forming dietary fiber is in the form of granules which are coated with a cellulose polymer coating, the composition optionally being compressed into a tablet form; such a PA1 method wherein the drug or therapeutic agent is in granular form, the granules being coated with a film of a cellulose polymer, the composition optionally being compressed into a table form; such a PA1 method wherein the drug or therapeutic agent is niacin; such a PA1 method wherein the niacin is present in amount between about 100 and about 200 mg/per unit dosage form; such a PA1 method wherein the composition is in tablet form; and such a PA1 method wherein the drug or therapeutic agent is an analgesic, an antihypercholesterolemic, a vitamin, a stimulant, an appetite suppressant, a mineral supplement, or a therapeutic peptide. PA1 a solid prolonged-release oral unit dosage composition for oral administration and ingestion in solid form and intended to be swallowed as such, which consists essentially of an effective dose of a biologically-absorbable therapeutic agent or drug in microsphere or nanosphere particle form, which is capable of being transported from the intestinal lumen or epithelium into the bloodstream in a matrix comprising a gel-forming dietary fiber, optionally in the form of a tablet; and such a PA1 composition wherein the nanosphere or microsphere contains a therapeutic peptide or protein and wherein the gel-forming dietary fiber is present in a pancreatic-enzyme activity-inhibitory amount so as to protect the peptide or protein from destruction by proteolytic degradation in the gastrointestinal tract upon oral administration. PA1 composition wherein at least the peptide or protein is coated with a protective hydrocolloid coating; such a PA1 composition wherein the peptide or protein is present in the form of microsphere or nanosphere particles which are capable of being transported from the intestinal lumen or epithelium into the bloodstream upon ingestion; and such a PA1 composition wherein gel-forming dietary fiber particles are coated with a hydrocolloid and optionally compressed into the form of a tablet. PA1 a method of reducing irritation of the gastrointestinal tract caused by oral administration of a nonsteroidal anti-inflammatory drug, which consists essentially of the step of administering the drug in an oral dosage form comprising a gel-forming fiber matrix for protection of the epithelium and gastrointestinal lining upon ingestion, the gel-forming fiber being present in an epithelium- and gastrointestinal lining-protective amount; and such a PA1 method wherein gel-forming dietary fiber particles are coated with a hydrocolloid film and optionally compressed into the form of a tablet; as well as such a PA1 method wherein gel-forming dietary fiber particles are coated with a cellulose polymer film and optionally compressed into the form of a tablet. PA1 composition wherein the gas released is carbon dioxide; such a PA1 composition wherein the mineral salt is a mineral carbonate or bicarbonate; such a PA1 composition wherein the mineral salt is calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate; such a PA1 composition wherein the acid is present in amount of about 1% to about 50% by weight; such a PA1 composition wherein the acid is a food-grade organic acid or phosphoric acid; such a PA1 composition wherein the gel-forming dietary fiber comprises about 30-40% by weight of the composition; such a PA1 composition wherein a soluble sugar is present in an amount of about 1% to about 12% by weight of the composition; such a PA1 composition wherein the gel-forming fiber is psyllium husk powder, guar gum, locust bean gum, acacia gum, gum arabic, xanthan gum, carrageenan gum, karaya gum, tragacanth gum, ghatti gum, pectin, a pectic substance, an algal polysaccharide, glucomannan, agar, or lignin, or a combination of more than one thereof; such a PA1 composition wherein at least the gel-forming dietary fiber is in the form of granules which are coated with a hydrocolloid film coating, the composition optionally being compressed into a tablet form; and such a PA1 composition wherein the drug or therapeutic agent is in granular form, the granules being coated with a hydrocolloid film, the composition optionally being compressed into a tablet form.
According to the present invention, the presence of a mineral carbonate or bicarbonate in the formulation provides an improved hydration rate and helps to open up the selected solid unit dosage form involved, allowing for more rapid hydration which assists with controlled release of the biologically-absorbable therapeutic agent or drug contained therein, but may be used in lower percentages when more prolonged release is desired. Likewise, the physiologically-acceptable acid, e.g., the food-grade organic acid or phosphoric acid, has been found not to be absolutely essential, although it can be present to assist in providing an improved hydration rate and help to open up the tablet or other selected oral unit-dosage form involved when a quicker release of drug is desired. It is unnecessary when a more prolonged release is desired.
The employment of these ingredients, in the manner described, plus the precoating of one or both of the gel-forming fiber particles employed and the drug or other therapeutic agent particles involved, permits the percentage of fiber in the formulation to be lower, whereas the ratio of other excipients to fiber may be higher, and this precoating of the fiber and drug, as well as the additional variable and optional possible variations in the other ingredients present, provides an improved manner of dealing with the problem of getting the tablet or other oral unit dosage form to hydrate properly, albeit in a different manner according to the present invention, according to which the guar gum or other gel-forming fiber is actually employed to produce controlled release of the therapeutic agent or drug by controlling the rate of hydration of the fiber so that the gel fiber matrix remains relatively intact and may even pass entirely through the gastrointestinal tract, slowly releasing the therapeutic agent or drug as it passes through the system. Accordingly, according to the present invention, I have been able to utilize the long-outstanding problem of improper and incomplete dissolution of guar gum or other gel-forming fiber tablets or other pharmaceutical forms, as pointed out previously under the heading "Field of Invention and Prior Art", to advantage. Instead of hard tablets, granules, etc., which do not swell properly and in which the gel-forming fiber forms an impenetrable layer around a powder or other core which passes through the gastrointestinal tract undissolved, I have been able to produce controlled release of the therapeutic agent or drug from the gel-forming fiber matrix so that, as the gel-forming fiber matrix passes through the gastrointestinal tract, the therapeutic agent or drug is subjected to controlled release as desired, the expendable fiber matrix, especially when precoated, passing through the gastrointestinal tract and being eliminated in the feces after performing its predesignated function of producing predetermined controlled release of the therapeutic agent or drug as it passes through the gastrointestinal tract.
Many important and variable classes of therapeutic agents and drugs, including also peptides and liposoluble drugs, can be transported and subjected to controlled release according to the present invention, in which the percentage of the gel-forming fiber present, especially when precoated, and due to a different function than in previous developments, can be substantially lower than previously believed possible. The novel prolonged-release unit dosage form of the present invention releases the drug or other therapeutic agent in a manner which can be precontrolled and which does not require complete disintegration of the tablet or other oral unit dosage form involved, as previously believed, because the tablet or other unit dosage form need not break up in the gastrointestinal tract but rather can remain essentially solid until it is expelled therefrom, meanwhile controllably releasing the drug or other therapeutic agent on route to its point of elimination. Aside from the usual advantages of controllable prolonged release rate, the present invention also provides a way to protect peptides, proteins, liposoluble drugs, vitamins, and the like, from premature disintegration or deterioration while in the gastrointestinal tract, and for reducing irritation therein by non-steroidal as well as other anti-inflammatory and similar agents which are capable of producing gastric irritation and ulceration due to chronic therapy therewith over a period of time, as will be apparent to one skilled in the art.
The following additional comments are appropriate:
It is known that the particle size distribution of gel-forming fibers such as guar gum has a direct effect on viscosity. It has also been found that the finer the particle size of the guar gum or other gel-forming fiber, the more difficult or impossible it becomes to get tablets containing a high percentage of gel-forming fiber or gum to disintegrate, hydrate, or dissolve.
Gel-forming fibers such as guar gum have been used as tablet disintegrants, but at low levels, generally less than 5%, optimally around 3%. A disintegrant helps a tablet to break down and release the drug rapidly, usually within 20 minutes. As grades of gums or fibers increase in viscosity, the drug-release rate will generally decrease. The lower viscosity grades have a faster solution rate than higher viscosity grades. Therefore, it is necessary to be able to have a consistent granulation of gel-forming fiber or gum for a consistent release pattern of drug. This, in turn, leads to greater control over the viscosity of the tablet as it travels in the gastrointestinal tract. Generally speaking, disintegrating agents with the highest rates of water absorption produce the longest disintegration time, although this is also related to the percentage of disintegrant used in the formulation. Gel-forming fibers such as guar gum produce rapid dissolution (e.g., 20 minutes) when used at a 3% level in a formulation, but above a 5% level start locking up the tablet and slowing down dissolution, even preventing the tablet from completely dissolving or hydrating. I have turned this disadvantage into an advantage according to the present invention.
According to the present invention, which I consider to be an advancement in the art and a further extension of the invention of my previous U.S. Pat. No. 5,096,714, I combine in a unit dosage form, e.g., tablet, the gel-forming fiber and the drug or other therapeutic agent, and an amount of a mineral salt which releases a physiologically-acceptable gas upon ingestion, e.g., a mineral carbonate or bicarbonate, and may include other normal pharmaceutical excipients. For certain results, I also include a pharmaceutically-acceptable organic acid or phosphoric acid. Additionally, for certain purposes, I may also include a pharmaceutically-acceptable soluble sugar. In addition, I may coat the gel-forming fiber and optionally the drug or other therapeutic agent with a film of hydrocolloid, which may be the same or different than the gel-forming fiber employed. In this manner, I am able to control the release rate of the drug or other therapeutic agent from the fiber matrix over a wide range, which has not heretofore been possible using the same or similar ingredients. For example, for a relatively quick-release tablet, or a tablet in which the bulk of the therapeutic agent is released relatively quickly while the remainder is released over an approximately eight (8) hour period, I may coat the gel-forming fiber particles with a film of the hydrocolloid and I may employ a smaller amount of mineral carbonate or bicarbonate. I may also employ an organic acid, such as citric acid, or phosphoric acid, to facilitate a more rapid release. In addition, a soluble sugar may be included. When I wish an even more rapid release, I may provide the hydrocolloid film coating on both of the gel-forming fiber particles and the drug or other therapeutic agent particles. I may also increase the amount of the mineral carbonate or bicarbonate and the amount of the organic or phosphoric acid present in the composition. When I wish to provide a shorter release time for the drug or other therapeutic agent, I may employ a hydrocolloid film coating on only the gel-forming fiber particles, or eliminate the hydrocolloid film entirely, and/or reduce the amount of mineral carbonate or bicarbonate employed and/or eliminate the organic acid or phosphoric acid completely. In this manner, I am able to provide either extremely long-acting or relatively short-acting pharmaceutical forms, and to control the release times and rates by controlling the amounts of the ingredients employed, as just representatively pointed out in the foregoing.
The degree and rapidity of release of the drug or other therapeutic agent may also be controlled by controlling the relative amounts and types of gel-forming fiber employed, as it is well known that some are more soluble and swellable than others. The soluble and swellable types are of by far the greatest interest according to the invention. All in all, by exploiting the various possible variables as set forth in the foregoing, and as will be readily apparent to one skilled in the art, I am able to provide a unit dosage form from which the drug or other therapeutic agent is released in a controlled manner over an extremely wide range of time periods, with of course the ensuing result that the drug or other therapeutic agent is released to a different extent in different segments of the gastrointestinal tract.